ABSTRACT This proposal is to request support for a Keystone Symposia meeting entitled "Complex Traits: Biologic and Therapeutic Insights", organized by Trudy F.C. Mackay, Lon Cardon and David R. Cox, which will be held in Santa Fe, New Mexico from February 29 [unreadable] March 5, 2008. Most phenotypic variation in populations, including variation in susceptibility to common human diseases, is attributable to segregating alleles of multiple genes, whose expression is dependent on the environment. Rapidly increasing knowledge about variation in genome sequence and gene expression will facilitate understanding the relationships of genotype to complex phenotypes and the evolutionary mechanisms shaping variation for complex traits, in humans and model organisms. Major questions to be solved regarding the genetic architecture of complex traits include the following: the relative prevalence of common and rare variants; whether causal variation is typically regulatory or structural; how many segregating alleles affect any given trait and their pleiotropic effects on other traits; and the extent to which allelic effects depend on other segregating alleles and the environment. This meeting aims to address these questions by bringing together investigators from population and quantitative genetics, genomics, and with expertise in model systems and humans. PROJECT NARRATIVE Rapidly increasing knowledge about variation in genome sequence and gene expression and the development of new statistical methods will revolutionize our ability to identify causal genetic variants affecting common human diseases and disorders, and that contribute to adaptive evolution. Understanding the genetic basis of variation for complex traits and gene-environment interaction is critical for achieving the goal of personalized medicine, as well as for understanding adaptive evolution.